US3796800A - Anti-inflammatory triazole compositions and methods for using same - Google Patents

Anti-inflammatory triazole compositions and methods for using same Download PDF

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Publication number
US3796800A
US3796800A US00201143A US3796800DA US3796800A US 3796800 A US3796800 A US 3796800A US 00201143 A US00201143 A US 00201143A US 3796800D A US3796800D A US 3796800DA US 3796800 A US3796800 A US 3796800A
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compound
compounds
edema
rats
administered
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US00201143A
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Z Ariyan
M Kulka
W Harrison
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Uniroyal Chemical Co Inc
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Uniroyal Ltd Great Britain
Uniroyal Inc
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Assigned to UNIROYAL CHEMICAL COMPANY, INC., WORLD HEADQUARTERS, MIDDLEBURY, CT. 06749, A CORP. OF NEW JERSEY reassignment UNIROYAL CHEMICAL COMPANY, INC., WORLD HEADQUARTERS, MIDDLEBURY, CT. 06749, A CORP. OF NEW JERSEY ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: UNIROYAL, INC., A NEW YORK CORP.
Assigned to UNIROYAL CHEMICAL COMPANY, INC. reassignment UNIROYAL CHEMICAL COMPANY, INC. ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: UNIROYAL, INC., A NJ CORP.
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Definitions

  • the invention relates to thiazole derivatives which are useful as antiinflammatory agents, i.e., they prevent and/or inhibit the formation of granuloma tissue in animals. Accordingly, the invention is, in one aspect thereof, a method of preventing and/or inhibiting the formation of granuloma tissue in animal subjects. In a, second aspect, the invention is a class of pharmaceutical compositions containing the present thiazole derivatives.
  • This compound contains an acidic function, and the acidic function has been postulated as being responsible for the reactivation of latent ulcers. Thus, acidic moieties are considered to be ulcerogenic.
  • the compounds of the present invention are nonacidic compounds, and thus do not suffer from the drawbacks of the known compounds.
  • the invention provides a safe and effective method of preventing and inhibiting the formation of granuloma tissue in an animal subject. This is achieved by administering to an animal subject a therapeutically effective amount of at least one compound selected from a very large group of thiazole derivatives, including Z-aminothiazoles and 2- (N-morpholino)-thiazoles.
  • the amount administered will be from about 0.1 to mg./kg./ day of body weight, preferably from about 10 to 25 mg./kg./day.
  • the amount will be from about 0.1 to 1 mg./kg./day, preferably from about 0.25 to 0.6 mg./kg./day.
  • the invention further provides a new class of pharmaceutical compositions comprising said thiazole derivatives which are effective as antiinflarnmatory agents.
  • R is lower alkyl (e.g., CH or N-aminocarbamoyl; R and R' are independently selected from the group consisting of hydrogen, lower alkyl (e.g., C H and lower acyl (e.g., -COCH and R is hydrogen, CONHR or CONR R wherein R is phenyl, mono-, dior tri- (lower)alkylphenyl (e.g., o-tolyl, o-ethylphenyl, 2,6-di-methyl [and ethyl] phenyl and 2,4,6-trimethy1- phenyl), benzyl, halophenyl (e.g., o-chlorophenyl), cyclohexyl or amino; R is lower alkyl (C -C R is lower alkyl (C -C or phenyl; or R and R together with the nitrogen atom form a morpholino ring
  • the 2-(N-morpholino)thiazole derivatives which are among those used in the present methods are those hav- 3 wherein R is a lower alkyl group (e.g., methyl or ethyl) and R is --H, CONHC H or --CONHC H (2,6-diethyl); and pharmaceutically acceptable acid addition salts thereof such as the hydrochloride.
  • compositions according to the invention comprise, in combination, a therapeutically efiective amount of at least one of the above-described thiazole derivatives and a pharmaceutically acceptable carrier and/or diluent therefor.
  • the composition will comprise, in addition to the active ingredients, fillers, binders and diluents such as lactose, methylcellulose, talc, gum tragacanth, gum acacia, agar, polyvinylpyrrolidone, stearic acid, and/or corn starch, etc.
  • a filler such as sodium carboxymethylcellulose and/or syrup, e.g., a glycerine based syrup.
  • the composition will comprise, in addition to the active ingredient, a suitable solvent or other liquid such as a saline solution.
  • a topical ointment the composition will comprise, in addition to the active ingredient, a vehicle such as petroleum jelly or hydrophilic petrolatum.
  • the most preferred compound from among all those of the Formula A is 2 amino-2',4,4,6'-tetramethyl 5-thiazolecarboxanilide, i.e., the compound wherein R is methyl, R" and R' are hydrogen, and R is CONHR in which R is 2,4,6-trimethylphenyl.
  • This compound in the rat (at a dose of 200 mg./kg.) produces a reduction of 77% in carrageenin induced edema.
  • the most preferred compound from among all those of the Formula B is Z-(N-morpholino)-4-methyl-5-thiazolecarboxanilide, i.e., the compound wherein R is methyl and R is CONHC H
  • the compound in the rat (at a dose of 200 mg./Hg.) produces a reduction of 52% in carrageenin induced edema.
  • the Z-aminothiazoles of the present invention can be prepared by the methods disclosed in the Kulka et al patent.
  • One method is the reaction sequence which comprises reacting an a-halocar-bonyl compound of the formula:
  • R, R', R" and R' are as defined above and Hal is a halogen, to form the hydrohalide salt of the 2-aminothiazole derivative of the Formula A:
  • TIT I, R (A) and this enables their preparation from crude a-halocarbonyl compound because the impurities present in such a crude starting material are usually benzene-soluble and may be washed out of the end product.
  • reaction may be carried out in one step by mixing together the thioamide, the unhalogenated precursor of the u-halocarbonyl compound, i.e.,
  • the 2-(N morpholido) thiazoles of the present invention can be prepared by the same methods as are used to prepare the Z-aminothiazoles, except that a thioamide of the formula:
  • the crude product (815 g., 87% yield) started to melt at 211 and finally melted with decomposition at 262. Recrystallization from ethanol gave 692 g. of 2- amino-4-methyl-S-thiazolecarboxanilide which started to melt at 221 or higher. Yield: 74%. (The purified base partially melts at 222223 and then becomes solid again. Decomposition occurs slowly as the temperature is raised and the final melting point is variable.)
  • Method B A reaction mixture of a-chloroacetoacetoacetanilide (528 g., 2.5 mol), thiourea (190 g., 2.5 mol) and water (1600 ml.) was stirred and heated at -90 until the solid dissolved (about one hour). The hot solution was filtered and the filtrate basified with a solution of concentrated ammonium hydroxide (28 to 30%) (203 ml.) and water (300 ml.). The white precipitate was filtered, washed with water and dried. The white product melted at 220-223 and weighed 526 g. or 90%.
  • a slurry of the crude hydrochloride in water was treated with aqueous ammonia to liberate the base.
  • the base was recrystallized from ethanol, in which it is only slightly soluble to give white crystals (55 g. or 86% yield) which melted at 258-259 with decomposition.
  • EXAMPLE 16 4- (4-ethyl-2-thiazolyl morpholine hydrochloride 4-morpholinethiocarboxamide (20.0 g., 0.137 mole) and 1-cluloro-2-butanone (15.0 g., 0.141 mole) were heated in absolute ethanol (150 ml.) under reflux with stirring for two hours. Evaporation of the solvent under vacuum yielded crude 4-(4-ethyl-2-thiazolyl)morpholine hydrochloride (27 g., 84% yield). After recrystallization from ethyl acetate-absolute ethanol, the product melted at 159- 162.
  • the procedure used for measuring the inhibition of carrageenin-induced edema is a modification of the method of Winter, et al., Proc. Soc. Exptl. Biol. Med. 111: 544 (1962).
  • the device used for measurement of the paw volume is an adaptation of the water displacement procedure described by Adamkiewicz, eta1., Can. J. Biochem. Physiol. 33: 332 (1955).
  • the present compounds were studied for their effectiveness in preventing the edema caused by the intraplantar injection of 0.05 ml. of a sterile 1.0% solution of carrageenin.
  • the present compounds were administered orally one hour prior to the injection of the carrageenin into the left hind paw of rats. At peak swelling time (3 hours) the volume of edema was calculated by differential paw volumes.
  • the compounds numbered 4, 6, 9, 11, 13 and 17 were selected for further study to de- 70 termine the ED in edema reduction.
  • a group of normal rats was injected with carrageenin to induce edema.
  • the rats were treated with varying amounts of the above-described six compounds, and the ED was determined.
  • Table VIII gives the results of the test on Compounds 4, 6, 9, 11 and 17 using varying doses to determine the ED in local vs. systemic edema.
  • test compounds were added directly to the 1% carrageenin solution and injected in a volume of 0.5 ml. into the plantar tissue of the left hind paw.
  • a group of control animals received carrageenin only. Three hours later the edema was measured.
  • Antiinflammatory or irritant effect was calculated as the percent increase or decrease in edema between the control groups and the treated groups.
  • Ten rats were used per group. The calculated ED was based on the number of animals in each group which showed an incerase or decrease of at least 25% change from the mean control values.
  • a dose of 3 mg./kg. is sufiicient to cause a 40% reduction in granuloma formation in 50% of the test animals.
  • the adjuvant-induced arthritis test was also conducted in rats using Compound 4. This test requires one month (from 0 to day 31). In the first seventeen days (0-17), the disease is ,in a developing stage, while for the remainder of the month (18 31) the disease is fully developed. The results of this test, given in terms of percent reduction of swelling in the hind paw of the rat are shown in Table IX.
  • the method is essentially that of Newbould, Brit. J. Pharmacol. 21: 127, 1963.
  • the test compounds were studied in the developing arthritic state and in the established arthritic state. Separate gorups of twelve rats were administered the compounds orally using methylcellulose as the vehicle. In the study on the developing disease, administration of the test compounds begins on day 1 and on day 2 each animal is injected with 05 mL/k g. of a 0.5% suspension of heat-killed Mycobacterzlum tuberculosis into the plantar surface of the left hind paw. Foot volumes were measured by a water displacement device on the day of administration of the Mycobacterium and again on days 3, 10 and 17. The test compounds were administered once daily.
  • Body weights were recorded daily and the animals were examined for the spread of the inflammation and the degree of secondary lesions observed and scored as mild, moderate, or severe.
  • another group of rats are injected with the Mycobacterium and foot volumes are measured and after twenty days are again measured and administration of the test compounds begins and continues for eleven days. Foot volume measurements are repeated on day 27 and day 31.
  • the extent of the spread of the inflammation and the degree of lesions are recorded daily as are the body weights.
  • the effect of the test compounds is measured by the percentage reduction in left hind paw volumes as compared to the hind pawl volumes of the control groups.
  • Antipyretic activity The antipyretic activity of Compound 4 was evaluated in rats. Groups of five rats each were made hyperthermic by the subcutaneous injection of 1 ml./100 grams of body Weight of a 10% brewers yeast suspension. A control group of five rats received the brewers yeast and was dosed orally with methylcellulose (.025% Compound 4 was administered at 100 and 200 mg./kg. orally and phenylbutazone was given at 100 mg./kg. and studied in a parallel assay. Temperatures were measured at the time of yeast injection and seventeen hours later the temperatures were again recorded and the degree of hyperthermia evaluated. Drugs were then administered and the temperatures were again taken one and one-half hours after drug administration. The degree of antipyresis was evaluated by using the number of animals out of five which exhibited a 1 fall in body temperature. Compound 4 at 100 and 200 mg./kg. did not produce a significant antipyresis.
  • the compounds of the present invention may be administered to an animal subject in any of a number of forms and via any of several routes.
  • the compounds or compositions thereof may be orally administered in the form of tablets, pills, capsules, or in the form of a suspension.
  • the compounds may also be administered parenterally in the form of an injectable solution or suspension.
  • the compounds or compositions thereof may also be administered topically, in the form of an ointment or rectally, in the form of a suppository.
  • the compounds or compositions When orally administering the compounds or compositions, use can be made of a tablet, pill or capsule consisting entirely of the desired compound, although ordinarily, a composition comprising an effective amount of the compound and varying amounts of one or more physiologically inert materials such as carriers, vehicles, binders and the like will be used. Additionally, the compounds may be orally administered in the form of a suspension thereof in a suitable vehicle such as a syrup.
  • parenterally administering the compounds or compositions use may be made of a parenteral solution or suspension of the compound in a suitable solvent or suspension medium.
  • the compounds of the present invention may also be administered rectally in the form of a suppository comprising an effective amount of the desired compound and a suitable vehicle such as petroleum jelly.
  • the compounds of the present invention may be applied topically in the form of an ointment, salve, cream of lotion comprising an effective amount of the desired compound and a suitable vehicle such as petroleum jelly, etc.
  • EXAMPLE 20 Tablets may be prepared by the compression of a wet granulation containing the following:
  • a liquid suspension for oral administration may be prepared in the following formulation:
  • DFC Dry filled capsules
  • Dosage 1 capsule three times a day.
  • EXAMPLE 23 An ointment for optical use may be prepared using the following formulation: Ingredients: Gm. in each Compound No. 4 5 Hydrophilic petrolatum USP q.s 100 Dosage: To be applied to infiammed skin areas as needed.
  • a parenteral suspension for intra-muscular administration may be prepared in the following formulation:
  • R is 13 or CONHNH R" is hydrogen, C H or COCH R' is hydrogen, C H or -OOCH and R is CONHR1 in which R is phenyl, o-tolyl, o-ethylphenyl, 2,6-dimethylphenyl, 2,6 diethylphenyl, 2,4,6 trimethylphenyl, benzyl, o-chlorophenyl, cyclohexyl or amino; or
  • said orally administrable dosage form is a pill, tablet or capsule.
  • parenterally administrable dosage form is a solution or suspension.
  • a method as claimed in claim 1 wherein said therapeutically effective amount is from 0.1 to 100 mg./kg. of body weight of said animal per day.
  • a method as claimed in claim 11 wherein said amount is to 25 mg./kg. of body weight per day.
  • a method as claimed in claim 13 wherein said therapeutically effective amount is from 0.1 to l mg./kg. of body weight of said animal per day.
  • a pharmaceutical preparation in dosage unit form adapted for administration to obtain an antiinflarnmatory eifect comprising an antiinflammatory-effective nontoxic amount within the range from about 0.1 to about 100 mg./kg. of body weight of a compound having the formula as hereinafter set forth:
  • R is lower alkyl, or N-aminocarbamoyl
  • R" is hydrogen, lower alkyl or lower acyl
  • R" is hydrogen, lower alkyl or lower acyl
  • R CONHR or CONR R wherein R is phenyl, mono-, di-, or tri-(lower)-alkylphenyl, benzyl, halophenyl, cyclohexyl or amino, R is lower alkyl and R is lower alkyl or phenyl or a pharmaceutically acceptable acid addition salt thereof; in combination with a physiogolically acceptable carrier and/or diluent therefor.
  • composition as claimed in claim 18 wherein said orally administrable dosage form is a pill, tablet or capsule.
  • composition as claimed in claim 19 wherein said pill, tablet or capsule comprises 10-15 mg. of said compound.
  • composition as claimed in claim 18 wherein said orally administrable dosage form is a solution or suspension.
  • composition as claimed in claim 15 in a parenterally administrable dosage form is administrable.
  • composition as claimed in claim 23 wherein said parenterally administrable dosage form is a suspension.
  • composition as claimed in claim 24 wherein said suspension comprises about 1.66 mg. of said compound per cc. 1
  • composition as claimed in claim 15 in a topically administrable dosage form is a composition as claimed in claim 15 in a topically administrable dosage form.
  • composition as claimed in claim 27 wherein said ointment comprises about 5 gm. of said compound per gm. of total ointment.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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  • Thiazole And Isothizaole Compounds (AREA)
US00201143A 1971-11-22 1971-11-22 Anti-inflammatory triazole compositions and methods for using same Expired - Lifetime US3796800A (en)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4308391A (en) * 1979-10-01 1981-12-29 Monsanto Company 2-Amino-4-substituted-thiazolecarboxylic acids and their derivatives
US6596746B1 (en) 1999-04-15 2003-07-22 Bristol-Myers Squibb Company Cyclic protein tyrosine kinase inhibitors
FR2842523A1 (fr) * 2002-07-17 2004-01-23 Sanofi Synthelabo Derives d'acylaminothiazole, leur preparation et leur application en therapeutique
US20040054186A1 (en) * 1999-04-15 2004-03-18 Jagabandhu Das Cyclic protein tyrosine kinase inhibitors
US20040174771A1 (en) * 2002-03-08 2004-09-09 Pierre Alinat Panoramic audio device for passive sonar
US20050176965A1 (en) * 2004-02-06 2005-08-11 Bang-Chi Chen Process for preparing 2-aminothiazole-5-carboxamides useful as kinase inhibitors

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3879531A (en) * 1972-07-17 1975-04-22 Uniroyal Inc 2-aminothiazoles compositions and methods for using them as psychotherapeutic agents
GB8302591D0 (en) * 1983-01-31 1983-03-02 Fujisawa Pharmaceutical Co Thiazole derivatives

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1546183A (fr) * 1966-12-07 1968-11-15 Uniroyal Inc Carboxamidothiazoles, leurs substituants et dérivés, leurs procédés de fabrication ainsi que leurs applications et procédés d'application agriculturaux
GB1290841A (en)) * 1968-07-05 1972-09-27

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4308391A (en) * 1979-10-01 1981-12-29 Monsanto Company 2-Amino-4-substituted-thiazolecarboxylic acids and their derivatives
US6979694B2 (en) 1999-04-15 2005-12-27 Bristol-Myers Squibb Company Cyclic protein tyrosine kinase inhibitors
US6596746B1 (en) 1999-04-15 2003-07-22 Bristol-Myers Squibb Company Cyclic protein tyrosine kinase inhibitors
US20040024208A1 (en) * 1999-04-15 2004-02-05 Jagabandhu Das Cyclic protein tyrosine kinase inhibitors
US20040054186A1 (en) * 1999-04-15 2004-03-18 Jagabandhu Das Cyclic protein tyrosine kinase inhibitors
US20040073026A1 (en) * 1999-04-15 2004-04-15 Jagabandhu Das Cyclic protein tyrosine kinase inhibitors
US20040077875A1 (en) * 1999-04-15 2004-04-22 Jagabandhu Das Cyclic protein tyrosine kinase inhibitors
US7091223B2 (en) 1999-04-15 2006-08-15 Bristol-Myers Squibb Company Cyclic protein tyrosine kinase inhibitors
EP3222619A1 (en) * 1999-04-15 2017-09-27 Bristol-Myers Squibb Holdings Ireland Cyclic protein tyrosine kinase inhibitors
US20050261305A1 (en) * 1999-04-15 2005-11-24 Jagabandhu Das Cyclic protein tyrosine kinase inhibitors
US8716323B2 (en) 1999-04-15 2014-05-06 Bristol-Myers Squibb Company Cyclic protein tyrosine kinase inhibitors
US9382219B2 (en) 1999-04-15 2016-07-05 Bristol-Myers Squibb Company Cyclic protein tyrosine kinase inhibitors
US20060079563A1 (en) * 1999-04-15 2006-04-13 Jagabandhu Das Cyclic protein tyrosine kinase inhibitors
US20050288303A1 (en) * 1999-04-15 2005-12-29 Barrish Joel C Cyclic protein tyrosine kinase inhibitors
US7125875B2 (en) 1999-04-15 2006-10-24 Bristol-Myers Squibb Company Cyclic protein tyrosine kinase inhibitors
US7153856B2 (en) 1999-04-15 2006-12-26 Bristol-Myers Squibb Company Cyclic protein tyrosine kinase inhibitors
US7189854B2 (en) 1999-04-15 2007-03-13 Bristol-Myers Squibb Company Cyclic protein tyrosine kinase inhibitors
US8993567B2 (en) 1999-04-15 2015-03-31 Bristol-Myers Squibb Company Cyclic protein tyrosine kinase inhibitors
US20040174771A1 (en) * 2002-03-08 2004-09-09 Pierre Alinat Panoramic audio device for passive sonar
FR2842523A1 (fr) * 2002-07-17 2004-01-23 Sanofi Synthelabo Derives d'acylaminothiazole, leur preparation et leur application en therapeutique
US7652146B2 (en) * 2004-02-06 2010-01-26 Bristol-Myers Squibb Company Process for preparing 2-aminothiazole-5-carboxamides useful as kinase inhibitors
US20050176965A1 (en) * 2004-02-06 2005-08-11 Bang-Chi Chen Process for preparing 2-aminothiazole-5-carboxamides useful as kinase inhibitors

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DE2257091A1 (de) 1973-05-24
GB1407856A (en) 1975-09-24
CA1009957A (en) 1977-05-10
JPS4861608A (en)) 1973-08-29
FR2160959B1 (en)) 1975-10-31
AU4908672A (en) 1974-05-23
AU477155B2 (en) 1976-10-14
FR2160959A1 (en)) 1973-07-06

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